Folate Therapy

Folate therapy replaces folic acid (vitamin B9) to correct deficiency, treat megaloblastic anaemia, support high red cell turnover and prevent neural tube defects. Folic acid is the stable synthetic form. Folinic acid (calcium folinate, leucovorin) is a reduced, active form used to rescue cells from antifolate toxicity.

Mechanism. Folate is reduced to tetrahydrofolate, a carrier of one-carbon units needed for purine and thymidylate synthesis. Deficiency slows DNA synthesis, causing megaloblastic changes in marrow and gut. Folinic acid bypasses dihydrofolate reductase, so it works despite methotrexate, pyrimethamine and trimethoprim.

Causes of deficiency. Poor diet, alcohol, malabsorption, increased demand (pregnancy, haemolysis, chronic inflammation), and drugs (methotrexate, trimethoprim, phenytoin, sulfasalazine).

Pharmacokinetics. Absorbed in the proximal small bowel; stored in the liver (several months); excreted in urine.

Folic acid dosing.

• Treatment of deficiency or megaloblastic anaemia: 5 mg orally daily for 4 months, or until the cause is corrected.
• Periconceptional prevention: 400 micrograms daily from before conception to 12 weeks; 5 mg daily when the risk of a neural tube defect is raised (previous affected pregnancy, anticonvulsants, diabetes, obesity, malabsorption).
• Chronic haemolysis, including sickle cell disease: 5 mg daily (1 mg in young children).
• Children: 5 mg daily from 1 year of age for treatment; 500 micrograms/kg daily in infants.
• Methotrexate toxicity prevention in inflammatory disease: folic acid 5 mg once weekly, on a different day from methotrexate.

Folinic acid dosing.

• Rescue after high-dose methotrexate: 15 mg orally or intravenously every 6 hours, starting 24 hours after the start of the methotrexate infusion and continuing until the methotrexate level falls under the safe threshold (dose adjusted to the level).
• Accidental or toxic methotrexate exposure: the same 15 mg regimen, with the dose raised in line with the level.
• Pyrimethamine for toxoplasmosis: folinic acid 10 to 25 mg daily.
• Trimethoprim-sulfamethoxazole toxicity with marrow suppression: folinic acid 5 to 15 mg daily.

Methylfolate. Used in some regions for patients with proven MTHFR deficiency; no clear benefit over folic acid.

• First-line. Folic acid for megaloblastic anaemia from folate deficiency, haemolytic anaemias, pregnancy prevention and malabsorption.
• Alternative. Folic acid prophylaxis in sickle cell disease and chronic haemolysis; weekly folic acid with methotrexate.
• Specialist. Folinic acid for methotrexate rescue, high-dose therapy, pemetrexed premedication and toxoplasmosis therapy; combined with fluorouracil in colorectal cancer regimens.
• Emergency. Folinic acid for methotrexate overdose or toxicity, with glucarpidase 50 units/kg intravenously where available and for renal failure.

Principles. Check vitamin B12 before starting folic acid. If B12 is deficient or unknown in severe anaemia, give both. Do not give folic acid with the same-day methotrexate dose.

Contraindications. Untreated vitamin B12 deficiency (folic acid); megaloblastic anaemia of unknown cause until B12 is excluded; hypersensitivity. Folinic acid is not given by intrathecal injection.

Serious adverse effects. Folic acid is well tolerated; rare hypersensitivity; high doses may mask B12 deficiency and may lower seizure control with phenytoin. Folinic acid: allergy, gastrointestinal upset; high doses may counteract antiepileptic drugs; excess may reduce chemotherapy effect.

Major interactions.

• Phenytoin, phenobarbital, primidone: folate lowers anticonvulsant levels and increases seizures; deficiency itself is caused by these drugs.
• Methotrexate, trimethoprim, pyrimethamine: antagonism of the antifolate effect.
• Sulfadoxine-pyrimethamine: folic acid at 5 mg daily reduces its antimalarial efficacy.
• Fluorouracil: folinic acid increases toxicity.

Common prescribing errors.

• Folic acid without checking B12.
• Folic acid taken the same day as methotrexate.
• Forgetting the 5 mg dose for high-risk neural tube defect prevention.
• Using folinic acid in the wrong context (for example, to treat simple deficiency).
• Stopping methotrexate rescue before levels fall.

Special groups.

• Pregnancy: 400 micrograms daily; 5 mg in high-risk women.
• Breastfeeding: compatible.
• Children: 5 mg daily; infants 500 micrograms/kg.
• Older adults: look for B12 deficiency and malabsorption.
• Kidney and liver: no adjustment; folinic acid rescue adjusted to the methotrexate level.
• East Africa: where intermittent preventive treatment in pregnancy uses sulfadoxine-pyrimethamine, a daily folic acid dose of 5 mg reduces its efficacy, so use 400 micrograms daily; high folate demand in sickle cell disease and malaria; dietary folate depends on vegetable intake.

Monitoring. Haemoglobin, reticulocytes, MCV and blood film; red cell folate; B12 level; methotrexate level for rescue; phenytoin level if on anticonvulsants.

Referral and escalation. Pancytopenia; neurological symptoms; failure to respond within 2 weeks; methotrexate toxicity with mucositis, myelosuppression or renal failure.

Comparison with alternative classes. Folate therapy corrects folate-dependent anaemia but not B12 deficiency, and is safer than transfusion for chronic deficiency; vitamin B12 and iron address different deficits.